Early recognition and characterization of soft tissue tumors is important for proper fetal and maternal care. Here, we present sonographic, fetal and postnatal MRI, and pathological findings of a rare case of congenital NTRK-rearranged malignant spindle cell sarcoma with TPM3-NTRK1 fusion in a male fetus.

Myoepithelial carcinoma is an ultra-rare pediatric solid tumor with no targeted treatments. Clinical implementation of tumor RNA sequencing (RNA-Seq) for identifying therapeutic targets is underexplored in pediatric cancer. We previously published the Comparative Analysis of RNA Expression (CARE), a framework for incorporating RNA-Seq-derived gene expression into the clinic for difficult-to-treat pediatric cancers. Here, we discuss a 4-year-old male diagnosed with myoepithelial carcinoma who was treated at Stanford Medicine Children's Health. A metastatic lung nodule from the patient underwent standard-of-care tumor DNA profiling and CARE analysis, wherein the patient's tumor RNA-Seq profile was compared to over 11,000 uniformly analyzed tumor profiles from public data repositories. DNA profiling yielded no actionable mutations. CARE identified overexpression biomarkers and nominated a treatment that produced a durable clinical response. These findings underscore the utility of data sharing and concurrent analysis of large genomic datasets for clinical benefit, particularly for rare cancers with unknown biological drivers.

Previous reports have described ETV6-NTRK3 fusion-positive gastrointestinal stromal tumors (GIST) in cases lacking KIT, PDGFRA, RAS pathway, or SDHx alterations. However, some investigators have questioned the rigor of these reports and the true existence of NTRK rearrangements in GIST. This study aims to (i) resolve whether NTRK gene rearrangements exist in GIST; (ii) review the relevant literature; and (iii) demonstrate a case of GIST with NTRK fusion.

A comprehensive literature review using PubMed identified additional NTRK fusion-reported cases. Under an institutional review board-approved protocol, we describe a patient with biopsy-proven GIST who underwent genomic and transcriptomic Clinical Laboratory Improvement Amendments-certified testing, precision-matched therapy, surgical resection, and pathologic analysis.

We identified 17 reported cases of GIST with NTRK fusions. Five studies reported GIST with KIT/DOG-1 expression by IHC, wild-type KIT/PDGFRA, and an ETV6-NTRK3 fusion, consistent with GIST. We demonstrate a case of a 72-year-old female after resection of a high-risk gastric GIST followed by 45 months of adjuvant imatinib. She developed recurrent disease, and biopsy revealed mixed epithelioid and spindleoid GIST with IHC expression of KIT (CD117) and DOG-1. Imatinib was reinitiated, but her disease progressed, prompting molecular testing for the first time. RNA sequencing identified an in-frame fusion of ETV6 with NTRK3. Larotrectinib, a pan-NTRK inhibitor, was initiated at a dose of 100 mg twice daily for 7 months, resulting in shrinkage in five tumors (range, 4.2%-77%). Surgical cytoreduction demonstrated a pathologic near-complete response (1% viable tumor cells).

Our findings confirm the existence of GIST with ETV6-NTRK3 fusion and demonstrate that these imatinib-resistant GIST may be exquisitely sensitive to tropomyosin receptor kinase inhibitors, although radiologic partial response may not be commensurate with pathologic responses.

Precision medicine programs like the Zero Childhood Cancer Program perform comprehensive molecular analysis of patient tumors, enabling detection of novel structural variants that may be cryptic to standard techniques. Identification of these variants can impact individual patient treatment, and beyond this establish new mechanisms of oncogenic activation. We have identified a novel internal tandem duplication (ITD) in the receptor tyrosine kinase (RTK), NTRK2, in a patient with FOXR2-activated CNS neuroblastoma. The ITD spans exons 10-13 of NTRK2 encoding the transmembrane domain. NTRK2 ITD is transforming and sensitive to TRK inhibition. In silico structural predictions suggested the duplication of an alpha-helix region and juxtaposed tyrosine residues that play a role in facilitating autophosphorylation. Consistent with this, mutation of these residues inhibited cellular transformation. This is the first report of an ITD spanning the transmembrane domain of an RTK, characterizing an additional mechanism by which RTKs are activated in cancer.

Signal transducer and activator of transcription 3 (STAT3) is a promising yet challenging anticancer drug target due to its complex signaling and limited "druggability". To this end, we herein highlight a target engagement-focused screening and optimization pipeline pursuing the discovery of novel STAT3 inhibitors. From a STAT3 differential scanning fluorimetry high-throughput screen, we identified compounds that appeared to stabilize STAT3 toward thermal aggregation and moderately inhibited cellular STAT3 activity. Subsequent evaluation using complementary and orthogonal assays revealed their high affinity for tropomyosin receptor kinase A (TrkA). Applying a similar target engagement-inspired approach, we refined inhibitor binding and selectivity toward TrkA, showing efficacy in cellular TrkA cancer models. Top compound, PI-15, demonstrated successful target engagement in a cellular thermal shift assay and potently inhibited TrkA activity in cancer cells. These approaches highlight the importance of prioritizing rigorous target engagement validation early in the drug discovery pipeline, resulting in promising new inhibitors.

A growing body of research suggests a bidirectional interaction between cancer and the nervous system. Neural cells exert their effects on tumors by secreting neurotransmitters and cell adhesion molecules, which interact with specific receptors on tumor cells to modulate their behavior. Conversely, tumor-secreted factors, particularly including inflammatory factors, can alter neural activity and increase neuronal excitability, potentially contributing to neurological manifestations such as epilepsy. The immune system also serves as a crucial intermediary in the indirect communication between cancer and the nervous system. These insights have opened promising avenues for novel therapeutic strategies targeting both tumors and their associated neurological complications. In this review, we have synthesized the key biological mechanisms underlying cancer-nervous system interactions that have emerged over the past decade. We outline the molecular and cellular pathways mediating this cross-talk and explore the clinical implications of targeting the nervous system to suppress tumor growth and metastasis, mitigate neurological complications arising from cancer progression, and modulate the immune response through neural regulation in the context of cancer therapy.

Larotrectinib is the first-in-class, highly selective TRK inhibitor with demonstrated efficacy in various TRK fusion solid tumours. We report the efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal (GI) cancer.

Patients with TRK fusion GI cancer from NAVIGATE (NCT02576431) were included. Response was independent review committee (IRC)-assessed per RECIST v1.1.

As of July 2023, 44 patients were enrolled. Tumour types included colorectal (CRC; n = 26), pancreatic (n = 7), cholangiocarcinoma (n = 4), gastric (n = 3), and one each of appendiceal, duodenal, oesophageal and hepatic cancers. Of the 26 patients with CRC, 16 (62 %) had known microsatellite instability-high (MSI-H) status. For the 43 IRC-eligible patients, overall response rate was 28 % (95 % confidence interval [CI] 15-44) for all patients and 44 % (95 % CI 24-65) for those with CRC. In patients overall and in those with CRC, median duration of response was 27 months (95 % CI 6-not estimable [NE]) and 27 months (95 % CI 6-NE), median progression-free survival was 6 months (95 % CI 5-9) and 7 months (95 % CI 6-NE), and median overall survival was 13 months (95 % CI 7-29) and 29 months (95 % CI 7-NE), respectively. Grade 3/4 treatment-related adverse events (TRAEs) occurred in seven (16 %) patients. There were no deaths due to TRAEs.

Larotrectinib demonstrated long durability, extended survival and manageable safety in patients with TRK fusion GI cancer, including those with MSI-H CRC. This supports the wider adoption of next-generation sequencing testing for NTRK gene fusions in patients with GI cancer.

Fibroblast growth factor receptor (FGFR) 4 is overexpressed in gastric cancer (GC) and is a potential therapeutic target for GC. Since the FGF/FGFR signaling is involved in tumor microenvironment inducing the formation of an immunosuppression, lenvatinib is expected to inhibit FGFR4 leading to reduced tumor PD-L1 levels and regulatory T cell (Treg) infiltration, improving pembrolizumab efficacy. This study explored the background of the molecular mechanisms underlying the therapeutic efficacy of lenvatinib plus pembrolizumab.

Expression of FGFR4 and its specific ligand FGF19 was assessed by immunohistochemical staining and clinicopathological relevance was also examined. The effect of lenvatinib on FGF19-FGFR4 signaling was evaluated using cellular experiments. Lastly, the expression of FGFR4 on Treg cells was evaluated by immunostaining and flow cytometry. The Cancer Genome Atlas cBioPortal and Gene Expression Omnibus microarray databases were accessed to support these results.

High FGFR4 expression was associated with histological type and venous invasion and predominantly detected in human epidermal growth factor receptor 2 and Epstein-Barr virus-positive GC. Bioinformatics data suggested that FGF19-FGFR4 signaling was activated in GC, and cellular experiments showed that lenvatinib reduced FGFR4 and PD-L1 expression in GC cells. Results of integrating various analyses suggested that FGFR4 did not seem to be enough expressed on Treg cells in GC.

The FGF19-FGFR4 signaling has a pivotal role in gastric tumorigenesis and may be involved in immunosuppression through PD-L1 modification. But, lenvatinib may not regulate immune editing by directly inhibiting FGFR4 on Treg cells.

Spitz lesions display a set of genetic alterations that differ from classical melanocytic lesions: examples include mutations in HRAS and fusions involving ALK, ROS1, MET, MAP3K8, BRAF, and the NTRK genes. We present a Spitz spindle cell/Reed nevus with atypical junctional features and an NTRK2 translocation in a patient of unusual age. The patient was a 61-year-old man with a pigmented brown flat 6 mm lesion growing on the skin over the left scapula. The lesion was composed of spindled and epithelioid melanocytes and was arranged in nests with some scattered focal pagetoid cells as well as intraepidermal nests at the center of the lesion and occasional mitotic figures. The melanocytes showed diffuse staining for pan-Trk antibodies. p16 staining was focally and weakly positive. The cells showed staining for HMB-45, MART-1, and tyrosinase, whereas they were negative for PRAME, ALK-1, and ROS-1 immunostaining. BAP-1 was preserved. Next-generation sequencing detected a SQSTM1::NTRK2 fusion and showed no alterations of ALK, ROS1, RET, NTRK1, and NTRK3 genes, as well as no pathogenic variants of BRAF. Fluorescent in situ hybridization showed NTRK2 translocation in all melanocytes evaluated. This case presents a Spitz nevus with a rare translocation in an older patient.

ATP-binding proteins (ABPs) form diverse and essential protein families across living organisms. Early life forms likely relied on simple chemical reactions for energy, but with the emergence of ABPs and their evolving functions, organisms became capable of more efficient energy storage and utilization, which drove the complexity of metabolic and life processes. By binding and hydrolyzing ATP through conserved structural motifs such as the Walker motifs, ABPs play critical roles in material transport, signal transduction, cellular structure maintenance, motility, and cell cycle regulation. Dysfunctions arising from mutations, deletions, or misregulation of ABPs are linked to a variety of human diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases. The growing recognition of ABPs' significance in disease progression highlights their relevance not only in basic biology but also in clinical applications, particularly as biomarkers and therapeutic targets. This review provides a comprehensive overview of human ABPs, detailing their structural and functional roles, their involvement in disease mechanisms, and the latest advances in understanding their clinical relevance. Additionally, it identifies current research gaps and offers new perspectives for future investigations and therapeutic strategies.

Colorectal cancer (CRC) is a common tumor of the digestive system. In recent years, CRC has had the fourth highest incidence and second highest mortality rate among tumors worldwide. Therefore, it is important to identify new molecular markers, and examine their relationship with the clinicopathological features and prognosis of CRC patients. This study examined the correlation between the expression levels of the tropomyosin receptor kinase C (TRKC) and neurotrophic factor-3 (NT-3) proteins, and the clinicopathological features and prognosis of CRC patients.

In total, 141 paraffin-embedded specimens from patients who had undergone radical surgical resection for CRC were analyzed. All CRC diagnoses were confirmed by pathological examination. Corresponding adjacent normal tissues served as controls. Immunohistochemical staining was employed to assess the expression of the TRKC and NT-3 proteins in both the CRC and adjacent normal tissues. A subsequent statistical analysis was conducted to explore the associations between the expression levels of these proteins, and the clinicopathological features and prognostic outcomes of CRC patients.

The expression level of TRKC was significantly higher in the CRC tissues than the adjacent normal tissues, while the expression level of NT-3 was significantly lower in the CRC tissues than the adjacent normal tissues, and the observed differences were statistically significant (P<0.001). Notably, TRKC expression was significantly correlated with the tumor site (P<0.05), lymph node metastasis (P<0.05), tumor node metastasis (TNM) stage (P<0.01), serum carcinoembryonic antigen (CEA) level (P<0.01), and serum carbohydrate antigen 19-9 (CA199) level (P<0.05). The patients with positive TRKC had significantly shorter overall survival (OS) and progression-free survival (PFS) times than those with negative TRKC expression (P<0.001). Further, NT-3 expression was significantly associated with lymph node metastasis (P<0.05), distant metastasis (P<0.05), TNM stage (P<0.05), and serum CEA level (P<0.05). The patients with positive NT-3 expression had prolonged OS and PFS compared to those with negative NT-3 expression (P<0.01). The Cox proportional hazards regression model revealed that TRKC expression had a hazard ratio (HR) of 2.679 (P<0.01), while NT-3 expression had a HR of 0.433 (P<0.05).

We found that the TRKC and NT-3 proteins were closely associated with the occurrence, metastasis, invasion, and tumor marker levels of CRC, and can be used as independent predictors of prognosis in patients with CRC. TRKC mainly indicates a poor prognosis in CRC, while NT-3 indicates a good prognosis.

Background: The role of extracellular matrix adhesion components in modulation of the treatment sensitivity of ovarian cancer (OC) cells is not well understood. Methods and Results: Analysis of ovarian cancer TCGA gene expression datasets revealed an inverse correlation between genes involved in cell-cycle progression and extracellular matrix interactions, including laminin-binding receptor integrin β4, a major component of extracellular matrix adhesion. Gene ontology analysis also showed that in patient populations with low ITGB4 expression, cell cycle-related programs were activated, while in populations with high expression of ITGB4, the activation of these cell cycle programs was lower. Suppression of proliferation with the CDK4/6 inhibitor Palbociclib stimulated integrin β4 expression and induced protection against Cisplatin in cells naturally expressing low levels of integrin β4. Additionally, ovarian cancer patient-derived organoids showed reduced Cisplatin sensitivity when pretreated with Palbociclib. Our data also showed that integrin β4 overexpression decreased ovarian cancer cell proliferation and at the same time, attenuated Cisplatin response. Conclusions: In summary, our investigations support the idea that integrin β4, and likely its matrix ligands, play critical roles in the regulation of cellular growth and the chemoresistance of ovarian cancer cells.

Osteosarcoma (OS) presents significant treatment challenges due to chemoresistance. This study explores the molecular mechanisms underlying chemoresistance in OS, focusing on the novel fusion gene RPS27-RPS24. Using single-cell multi-omics techniques, we identified a significant upregulation of RPS27-RPS24 in chemoresistant OS cells. Our analyses revealed that RPS27-RPS24 enhances glutaminase (GLS)-mediated glutamine metabolism and inhibits copper-induced cell death, thereby promoting chemoresistance. In vitro experiments with adriamycin-resistant (ADMR) OS cells confirmed that overexpression of RPS27-RPS24 leads to increased cell viability and proliferation under chemotherapy. In vivo studies further validated these findings, demonstrating that targeting glutamine metabolism can reverse chemoresistance. Our results suggest that the RPS27-RPS24 fusion gene plays a critical role in OS chemoresistance through metabolic reprogramming, providing a potential therapeutic target for improving OS treatment outcomes. The application of multiple analytical techniques in this study (as shown in the upper image) and the hypothesized mechanism (as shown in the lower image).

Non-small cell lung cancer (NSCLC) is operated commonly by diverse genetic alterations, and oncogenic fusions represent a significant therapeutic role. Common fusions include ALK, ROS1, RET, and NTRK, signaling pathways in tumorigenesis. Recent advances in investigating tumor molecular biology include underlying fusions, including chromosomal rearrangements, highlighting their role as oncogenic drivers. The development of targeted therapies, such as tyrosine kinase inhibitors (TKIs), has impacted most patients' NSCLC treatment. Despite the greater profiles, such as remarkable efficiency and tolerable side effects compared to traditional chemotherapy, challenges, such as acquired mutations, lead to more ongoing research-optimized future NSCLC therapies.

Juvenile Xanthogranuloma (JXG) is a rare form of non-Langerhans cell histiocytosis. The most common known gene mutations affect the mitogen-activated protein (MAP) kinase, phosphoinositide 3-kinase (PI3K), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. We present a case of congenital JXG in a premature newborn from a dicygotic twin pregnancy with subdermal infiltrates on the chest, hepatosplenomegaly, ascites, pancytopenia, and petechiae on the abdomen and extremities. Next-generation sequencing of tissue from a subdermal infiltrate revealed a tropomyosin 3::neurotrophic tyrosine kinase receptor (TPM3::NTRK1) gene fusion. Therefore, a retrospective analysis of 34 additional non-Langerhans cell histiocytoses (16 JXG, 3 adult xanthogranuloma and 1 benign cephalic histiocytosis, both clinical subtypes of JXG, as well as 13 Rosai-Dorfman and 1 Erdheim-Chester disease) for NTRK1, 2 and 3 aberrations was performed. This analysis revealed an NTRK1 gene fusion in 4 additional JXGs and 1 adult xanthogranuloma. In conclusion, NTRK1 gene fusions are moderately common in JXG (6/21; 28.6% in our series). This finding places JXG in the category of proliferative diseases with one of the highest frequencies of NTRK gene rearrangements. Therefore, NTRK gene fusions should be included in a gene panel test for difficult-to-treat JXG. Given the potential of NTRK gene fusions as a therapeutic target, NTRK inhibitors may represent a novel effective treatment for JXG with a challenging clinical course.

Protein kinases represent a highly promising drug target, with over 80 drugs that target about two dozen different protein kinases have been approved by the US FDA, particularly in cancer treatment. Over the past decades, the unique structural characteristics of the thienopyrimidine ring system provide an adaptive platform for designing potent anticancer agents, especially various kinase inhibitors, which has attracted widespread attention. Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents. This article reviews the discovery, activity, and structure-activity relationships of antitumor kinase inhibitors based on the thienopyrimidine scaffold, and partially discusses the binding modes between thienopyrimidine derivatives and their kinase targets. By elucidating the application of thienopyrimidine derivatives as anticancer kinase inhibitors, this review aims to provide new perspectives for the development of more effective and novel kinase inhibitors.

Thyroid cancer prevalence has increased in the last few decades. Whereas the majority of well-differentiated histotypes have effective therapeutic options, the most advanced cases lacked successful treatment until recent years. Genomic alterations have emerged as targets for new anti-cancer drugs. This molecular knowledge is gradually being translated into sophisticated approaches for the stratification, management, and therapies of patients with thyroid carcinomas. The genomic characterisation of tumours in clinical assistance serves as a tool for enhancing the prognostic assessment of patients with thyroid cancer and predicting their responses to the agents. The MAPK pathway is the most predominantly activated molecular route in this cancer. Several drugs have been developed to inhibit this pathway at different levels. However, the acquired resistance that emerges is the main problem in their use. Other strategies targeting not only driver mutations but also those that confer aggressive behaviour on tumours can be potential targetable options. Due to the new therapies, patients with the most aggressive histotypes have improved survival rates. Adverse events, although manageable, have a high prevalence among the current therapies. Selective inhibitors, immunotherapies, and the combination of both will play a pivotal role in the treatment and the improvements in overall survival in thyroid cancer patients.

In recent years, pembrolizumab has demonstrated significant efficacy in treating tumors characterized by a high tumor mutational burden and high microsatellite instability. Tropomyosin receptor kinase (TRK) inhibitors have shown considerable efficacy against tumors harboring neurotrophic receptor tyrosine kinase (NTRK) fusion genes, highlighting the growing importance of personalized medicine in cancer treatment. Advanced sequencing technologies enable the rapid analysis of numerous genetic abnormalities in tumors, facilitating the identification of patients with positive biomarkers. These advances have increased the likelihood of providing effective, tailored treatments. NTRK fusion genes are present in various cancer types, including sarcomas, and the TRK inhibitors larotrectinib and entrectinib have been effectively used for these malignancies. Consequently, the treatment outcomes for NTRK fusion-positive tumors have improved significantly, reflecting a shift toward more personalized therapeutic approaches. This review focuses on NTRK fusion-positive sarcomas and comprehensively evaluates their epidemiology, clinical features, and radiological and histological characteristics. We also investigated the treatment landscape, including the latest methodologies involving TRK inhibitors, and discussed the long-term efficacy of these inhibitors, and their optimal order of use. Notably, larotrectinib has demonstrated a high response rate in infantile fibrosarcoma, and its efficacy has been confirmed even in advanced cases. However, further research is warranted to optimize treatment duration and subsequent management strategies. The accumulation of clinical cases worldwide will play a pivotal role in refining the treatment approaches for tumors associated with NTRK fusion genes.

The present study reports the case of a 25-year-old male patient with salivary gland secretory carcinoma (SC) with the ETV6::RET gene fusion. The patient presented with a left parotid mass and was treated using a superficial parotidectomy. Histological analysis of the tumor demonstrated a combination of cystic, follicular and trabecular patterns in cells, with eosinophilic secretions and a vacuolated cytoplasm. Tumor cells exhibited infiltrative growth into muscle and nerve tissues, accompanied by central stromal hyalinized sclerosis. Immunohistochemically, the tumor cells were positive for S-100, mammaglobin and GATA binding protein 3, and negative for DOG1. The results of the present case demonstrated that the patient possessed SC with the ETV6::RET gene fusion. Following the operation, the patient underwent radiotherapy, leading to a disease-free state at the last follow-up at 1 year and 3 months following surgery. A comprehensive review of 21 SC cases with this gene fusion, including the case reported in the present study, demonstrated that invasive growth, neural and lymphovascular invasion and hyalinized sclerosis were frequently seen on histology, and 11 cases (52%) exhibited advanced-stage disease (>T3 or M1). Thus, salivary gland SC with an ETV6::RET fusion may show infiltrative growth and may be more aggressive compared with salivary gland SC with an ETV6::NTRK3 fusion, which is often associated with an indolent clinical course. Therefore, confirmation of the genetic profile of SC is crucial for the prediction of patient prognosis and administration of an effective therapeutic course.

Detecting somatic structural variants (SVs), copy number variants (CNVs), and mutations in bone and soft tissue tumors is essential for accurately diagnosing, treating, and prognosticating outcomes. Optical genome mapping (OGM) holds promise to yield useful data on SVs and CNVs but requires fresh or snap-frozen tissues. This study aimed to evaluate the clinical utility of data from OGM compared with current standard-of-care cytogenetic testing. We evaluated 60 consecutive specimens from bone and soft tissue tumors using OGM and karyotyping, fluorescence in situ hybridization, gene fusion assays, and deep next-generation sequencing. OGM accurately identified diagnostic SVs/CNVs previously detected by karyotyping and fluorescence in situ hybridization (specificity = 100%). OGM identified diagnostic and pathogenic SVs/CNVs (∼23% of cases) undetected by karyotyping (cryptic/submicroscopic). OGM allowed the detection and further characterization of complex structural rearrangements including chromoanagenesis (27% of cases) and complex 3- to 6-way translocations (15% of cases). In addition to identifying 321 SVs and CNVs among cases with chromoanagenesis events, OGM identified approximately 9 SVs and 12 CNVs per sample. A combination of OGM and deep next-generation sequencing data identified diagnostic, disease-associated, and pathogenic SVs, CNVs, and mutations in ∼98% of the cases. Our cohort contained the most extensive collection of bone and soft tissue tumors profiled by OGM. OGM had excellent concordance with standard-of-care cytogenetic testing, detecting and assigning high-resolution genome-wide genomic abnormalities with higher sensitivity than routine testing. This is the first and largest study to provide insights into the clinical utility of combined OGM and deep sequencing for the pathologic diagnosis and potential prognostication of bone and soft tissue tumors in routine clinical practice.

Sarcomas are a rare and heterogeneous group of mesenchymal malignant tumors and account for approximately 1% of all adult cancers and around 20% of all pediatric solid tumors in Europe. Technology advances have enabled a more accurate and efficient characterization of the molecular mechanisms underlying the pathogenesis of sarcoma subtypes and revealed novel and unexpected therapeutic targets with prognostic/predictive biomarkers, namely the neurotrophic tyrosine receptor kinase (NTRK) gene fusion. The NTRK fusion assessment has recently become a standard part of management for patients with unresectable locally advanced or metastatic cancers and has been identified in various tumor types. In the more prevalent adult and pediatric sarcomas, NTRK fusions are present in 1% and 20%, respectively, and in more than 90% of very rare subsets of tumors. The inhibition of TRK activity with first-generation TRK inhibitors has been found to be effective and well tolerated in adult and pediatric patients, independently of the tumor type. Overall, the therapeutic benefit to those patients compensates for the difficulties of identifying NTRK gene fusions. However, the rarity and diagnostic complexity of NTRK gene fusions raise several questions and challenges for clinicians. To address these issues, an expert panel of medical and pediatric oncologists, radiologists, surgeons, orthopedists, and pathologists reviewed the recent literature and discussed the current status and challenges, proposing a diagnostic algorithm for identifying NTRK fusion sarcomas. The aim of this article is to review the updated information on this issue and to provide the experts' recommendations and practical guidance on the optimal management of patients with soft tissue sarcomas, infantile fibrosarcoma, gastrointestinal stromal tumors, and osteosarcoma.

Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with efficacy in children with TRK fusion tumors. We evaluated patient outcomes after elective discontinuation of larotrectinib in the absence of disease progression in a protocol-defined wait-and-see subset analysis of eligible patients where treatment resumption with larotrectinib was allowed if disease progressed. We also assessed the safety and efficacy of larotrectinib in all pediatric patients with sarcoma. This cohort included 91 patients (younger than 18 years) from two clinical trials: infantile fibrosarcoma (49), other soft tissue sarcomas or related mesenchymal tumors (41), and bone sarcoma (1). Treatment-related adverse events were of maximum grade 1 or 2 in 25% and 25% of patients, respectively. The overall response rate was 87% (95% CI, 78 to 93). In the wait-and-see analysis, 47 patients discontinued larotrectinib. Median time from discontinuation to disease progression was not reached. Sixteen patients had tumor progression during the wait-and-see period. All 16 patients resumed larotrectinib, and 15 (94%) achieved disease control, with 11 objective responses. Larotrectinib continues to demonstrate durable responses with favorable safety in children with TRK fusion sarcomas. Treatment discontinuation is feasible in select patients with objective response and clinical benefit noted in those who have disease progression after elective treatment discontinuation.

Neurotrophic tyrosine receptor kinase gene fusions are oncogenic drivers of various solid tumors. Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor approved for patients with TRK fusion cancer on the basis of single-arm trials. This study was a matched comparative effectiveness study of larotrectinib in clinical trials versus standard of care (SOC) in the real-world (RW) setting.

Adult patients with advanced/metastatic TRK fusion non-small cell lung cancer, colorectal cancer, soft tissue sarcoma, thyroid cancer, or salivary gland carcinoma were included. Deduplicated data from RW patients were from US and ex-US data sources. Patients in the larotrectinib cohort (pooled data from three trials, ClinicalTrials.gov identifiers: NCT02122913, NCT02576431, and NCT02637687) were matched 1:1 to RW patients on the basis of tumor type and line of therapy (LOT). A propensity score (weighting) model was used to balance key characteristics between cohorts. The primary outcome was overall survival (OS).

In total, 164 patients were matched 1:1 on tumor type and LOT (82 in each cohort). Balance in the baseline covariates was achieved after weighting. Larotrectinib-treated patients had longer OS (median, not reached [NR] v 37.2 months; hazard ratio [HR], 0.44 [95% CI, 0.23 to 0.83]), time to next treatment (median, NR v 10.6 months; HR, 0.22 [95% CI, 0.13 to 0.38]), duration of therapy (median, 30.8 v 3.4 months; HR, 0.23 [95% CI, 0.15 to 0.33]), and progression-free survival (median, 36.8 v 5.2 months; HR, 0.29 [95% CI, 0.18 to 0.46]) compared with RW patients after propensity score weighting.

In TRK fusion cancers, treatment with larotrectinib was associated with longer OS and prolonged time to event compared with SOC in all categories measured. These RW data provide context to support larotrectinib effectiveness in this population.

Xanthogranuloma is the most common category of histiocytic neoplasia, with a range of clinical behaviors from solitary cutaneous lesions to multiple cutaneous lesions and less frequent cases with evolution to disseminated disease. Solitary lesions make up 78% to 81% of total cases. We encountered 2 consecutive index patients with solitary cutaneous xanthogranuloma with NTRK overexpression by immunostaining and confirmed the presence of an NTRK1 fusion with both RNA and DNA sequencing. We screened 55 additional patients by pan-TRK immunostain, and found that 26 of 48 (54%) with solitary xanthogranulomas had TRK overexpression, whereas 0 of 7 (0%) multifocal or disseminated xanthogranulomas had TRK overexpression. We sequenced a subset of 23 patients with solitary xanthogranuloma. In all 16 patients with a positive pan-TRK immunostain, we confirmed the presence of an NTRK1 fusion using RNA and DNA sequencing. In all 7 patients that were negative by immunostain we identified no NTRK fusion by sequencing. All patients with a fusion identified by sequencing had overexpression of the NTRK1 RNA transcript relative to wild-type tumors with a mean 58-fold increase over wild-type tumors (P=8.77e-15). Further, all cases with fusions had a loss of the extracellular portion of NTRK1, and fusion partners were limited to TPM3, PRDX1, IRF2BP2, LRRIP1, and SQSTM1. DNA sequencing identified additional recurrent loss of function mutations in DNA methylation genes DNMT3A, KDM5D, and SETD2, as well as the MTOR-PI3K pathway gene FLCN. Recurrent copy number gains were detected in MTOR-PI3K pathway genes PIK3CG, IL10Ra, as well as transcriptional regulator PAX8. The frequency of NTRK1 fusions appears markedly higher in solitary compared with multifocal and disseminated xanthogranuloma (54% vs. 0%). The reduced proportion of NTRK1 fusions in disseminated cases relative to solitary cases suggests that NTRK1 fusions are less efficient than MAP kinase pathway point mutations at driving tumor evolution towards disseminated disease. As NTRK1 fusions are uncommon in other histiocytoses, pan-TRK immunostain may have utility to confirm the diagnosis of xanthogranuloma in a histiocytic lineage tumor and to screen for low-risk xanthogranuloma.

Digestive diseases are becoming an increasingly serious health burden, creating an urgent need to develop more effective treatment strategies. Probiotics and postbiotics have been extensively studied for their potential to prevent and treat digestive diseases. Growing evidence suggests that programmed cell death, especially apoptosis, is a critical mechanism influencing the molecular and biological aspects of digestive diseases, contributing to disease progression. Understanding the mechanisms and signaling pathways by which probiotics and postbiotics regulate apoptosis could reveal new therapeutic targets for treating digestive diseases. This review focuses on the beneficial effects of probiotics and postbiotics in regulating apoptosis across a range of liver diseases, including non-alcoholic fatty liver disease, liver injury, cirrhosis, and liver cancer. It also explores their effects on gastrointestinal diseases, such as colorectal cancer, colitis, gastrointestinal injury, and infectious diarrhea. Furthermore, some probiotics help balance the gut microbiota, enhance intestinal barrier function, and regulate the immune system, all of which are closely associated with apoptosis. Moreover, emerging technologies, such as encapsulation methods, have been developed to stabilize probiotics, primarily based on experimental findings from rodent and human studies.

Lung cancer is a prominent cause of cancer-related deaths globally, prompting exploration into the molecular pathways governing cancer cell signaling. Recent insights highlight the critical role of kinases in carcinogenesis and metastasis, particularly in non-small cell lung cancer (NSCLC), where protein kinases significantly contribute to drug resistance. These diverse enzymes catalyze protein phosphorylation and are implicated in cancer through misregulated expression, amplification, aberrant phosphorylation, mutations, and chromosomal translocations. Amplifications of kinases serve as important diagnostic, prognostic, and predictive biomarkers across various cancers. Notably, the Phosphatidylinositol 3-kinase (PI3K)/AKT pathway is crucial for the survival and proliferation of tumor cells. Novel therapeutic approaches are being explored to precisely target these pathways. Peptide-based therapies offer specificity and reduced toxicity compared to conventional treatments, while gene therapy targets abnormal genetic expressions. Advances in nanotechnology and CRISPR/Cas9 systems enhance gene delivery methods, holding promise for targeting specific molecular pathways in lung cancer treatment and minimizing systemic toxicity.

Penile cancer is a rare tumour with a global annual incidence of 0.2 to 1 case per 100,000 men. Sarcomatoid carcinoma (SC) of the penis, also known as carcinosarcoma, is a rare form of squamous cell carcinoma (SCC) of the penis, accounting for approximately 1-2% of all penile cancers. We report a case of SC of the penis in a 60-year-old man.

A 60-year-old male patient presented, with a penile glans nodule that had developed over a two-month period. The patient was employed in the agricultural sector and had a history of hypertension, which he asserted was effectively managed through pharmacological intervention. A specialist examination revealed an enlarged, cauliflower-shaped penile head with surface ulceration, approximately the size of 2 cm. He underwent a partial resection and bilateral inguinal and pelvic lymph node dissection. Histopathology demonstrated that the tumour cells were p63-positive, while p16 expression was absent. Vimentin and p53 were positive in the sarcomatous component, and the morphology and immunohistochemistry were consistent with penile SC. After six months, there was no evidence of disease progression.

The diagnosis of SC is challenging, and an accurate diagnosis is the first step towards successful treatment, which has a higher probability of success. It presents as a large, aggressive tumour, usually associated with lymph node metastasis and poor prognosis. Our case adds to the literature and reviews the treatment options for this rare disease and the poor prognosis associated with this malignancy.

The pervasive occurrence of nasopharyngeal carcinoma (NPC) is intricately linked to Epstein-Barr virus (EBV) infection, making EBV and its associated pathways promising therapeutic targets for NPC and other EBV-related cancers. Lytic induction therapy, an emerging virus-targeted therapeutic strategy, capitalizes on the presence of EBV in tumor cells to specifically induce cytotoxicity against EBV-associated malignancies. Despite the expanding repertoire of compounds developed to induce EBV lytic reactivation, achieving universal induction across all infected cells remains elusive. The inherent heterogeneity of tumor cells likely contributes to this variability. In this study, we used the NPC43 cell line, an EBV-positive NPC in vitro model, and single-cell transcriptomics to characterize the diverse cellular responses to EBV lytic induction. Our longitudinal monitoring revealed a distinctive lytic induction non-responsive cellular state characterized by elevated expression of SOX2 and NTRK2. Cells in this state exhibit phenotypic similarities to cancer stem cells (CSCs), and we verified the roles of SOX2 and NTRK2 in manifesting these phenotypes. Our findings reveal a significant challenge for lytic induction therapy, as not all tumor cells are equally susceptible. These insights highlight the importance of combining lytic induction with therapies targeting CSC-like properties to enhance treatment efficacy for NPC and other EBV-associated cancers.

The asymmetric hydrogenation (AH) of cyclic N-alkyl imines offers an elegant and efficient method to afford chiral amines, especially for S-nicotine and its derivatives. However, this approach remains an ongoing challenge due to undesirable coordination of pyridyl-containing substrates to the active metal catalyst. Herein, we disclose a manganese-catalyzed AH that allows access to S-nicotine and other chiral α-(hetero)aryl pyrrolidines and provides an example of a base-metal catalyst that displays superior performance to its noble metal counterparts.

Molecularly targeted therapies and immunotherapy are increasingly being employed in the treatment of aggressive, recurrent thyroid cancer. Evidence from several studies indicates that a significant proportion of tumor patients derive limited benefit from immunotherapy as a monotherapy, with vascular abnormalities in solid tumors contributing to immune evasion. Numerous studies, both domestic and international, have assessed the efficacy of combining immune checkpoint inhibitors with antiangiogenic agents across various tumor types. These studies suggest that such combination therapies are effective in controlling disease progression and extending survival, among other outcomes. Nevertheless, further research is warranted to substantiate these findings and optimize treatment protocols.

This study aims to describe a patient diagnosed with anaplastic thyroid carcinoma (ATC) combined with primary squamous cell carcinoma of the thyroid (PSCCT) and concurrent thyroid abscess. The patient experienced local recurrence and metastasis following surgical intervention, radiotherapy, and chemotherapy, and was found to be PD-1 negative. Disease progression was effectively controlled through combination therapy with anlotinib and tislelizumab. Additionally, a comprehensive review of the relevant literature was conducted.

The patient exhibited disease recurrence 8 months postoperatively, notwithstanding the administration of adjuvant radiotherapy and chemotherapy. The local recurrent mass demonstrated minimal reduction following 4 cycles of targeted therapy with anlotinib. However, subsequent treatment with a combination of anlotinib and tislelizumab resulted in a substantial reduction of the neck mass and enlarged cervical lymph nodes after 12 cycles. The patient tolerated the combination therapy well, experiencing no significant adverse effects aside from pronounced fatigue. Thus, the combination therapy with anlotinib and tislelizumab proved effective in controlling the disease.

The management of postoperative recurrence of ATC-PSCCT presents significant challenges, as recurrent tumors typically demonstrate increased aggressiveness and resistance to pharmacological interventions, necessitating multimodal therapeutic approaches. Tislelizumab, an immune checkpoint inhibitor, may facilitate immune-mediated tumor clearance through the activation of various immune cells, including natural killer cells and macrophages. Despite the patient's PD-1 negativity, the combination of anlotinib and tislelizumab may exert synergistic effects through distinct mechanisms, thereby potentially enhancing therapeutic efficacy. The integration of a multi-targeted tyrosine kinase inhibitor within this combination therapy regimen warrants further investigation.

Thrombospondin type 1 domain-containing 7 A (THSD7A) expression, an angiogenesis-related protein, has been implicated in various aspects of cancer progression, reflecting its potential as a prognostic marker for various cancers. Therefore, we investigated the prognostic value of THSD7A expression in colorectal cancer (CRC).

A total of 95 patients with CRC were included. The patients were stratified into two groups according to THSD7A expression status determined by immunohistochemistry [negative (no staining), and positive (expression ≥ 1% of cancer cells)]. The overall survival (OS) of prognostic subgroups was estimated by Kaplan Meier method. The prognostic value of THSD7A expression was evaluated by univariable and multivariable Cox regression models.

THSD7A was expressed in 42.1% of CRC patients. Patients with no THSD7A expression had inferior OS than patients with THSD7A expression (72.9 months vs. median OS was not reached, p = 0.001, respectively). Our multivariate analyses revealed that the independent predictors of OS were poor differentiation of tumor (HR: 2.603, p = 0.002), advanced stage (HR: 3.210, p < 0.001), and the loss of THSD7A expression (HR: 3.094, p = 0.001).

The present study showed that THSD7A expression could serve as a potential prognostic marker for CRC cancer. Further research is warranted to elucidate the exact underlying THSD7A-mediated cancer progression and to explore its clinical use in improving CRC prognostication and treatment strategies.

Traditional anatomic pathologic classification of cancer is based on tissue of origin and morphologic and immunohistochemical characterization of the malignant cells. With the technological improvements of massively parallel or next-generation sequencing, oncogenic drivers that are shared across different tumor types are increasingly being identified and used as pan-cancer biomarkers. This approach is reflected in the growing list of Food and Drug Administration-approved tumor-agnostic therapies, including pembrolizumab in the setting of microsatellite instability and high tumor mutational burden, larotrectinib and entrectinib for solid tumors with NTRK fusions, and combined dabrafenib-trametinib for BRAF V600E-mutated neoplasms. Several other biomarkers are currently under investigation, including fibroblast growth factor receptor (FGFR), RET, and ROS1 fusions; ERBB2 amplification; and mutations in the AKT1/2/3, NF1, RAS pathway and (mitogen-activated protein kinase (MAPK) pathway. As molecular assays are increasingly incorporated into routine tumor workup, the emergence of additional pan-cancer biomarkers is likely to be a matter more of "when" than "if." In this review, we first explore some of the conceptual and technical considerations at the intersection of surgical and molecular pathology, followed by a brief overview of both established and emerging molecular pan-cancer biomarkers and their diagnostic and clinical applications.

Cancer still represents a global health concern due to its high mortality and morbidity rates. Isatin-and pyrazole-based compounds have recently garnered interest as novel anticancer agents. A series of 15 novel spiroisatin pyranopyrazole derivatives were synthesized. Anticancer potential of synthesized agents against EBC-1, HT-29, A549, and AsPC-1 cell lines, representing cancers of the lung, colon, and pancreas, were evaluated using the MTT assay. The possible molecular mechanism contributing to antiproliferative activities of the most potent compounds was further investigated in silico by using SuperPred web server, a ligand-based tool. Docking and molecular dynamics (MD) simulation studies were carried out to investigate the binding affinity and key interactions of the agents with their predicted target. Among the tested compounds, four cyanide-containing derivatives 6c, 6d, 6f, and 6g with bromobenzyl, chlorobenzyl, p-tButyl benzyl and methylbenzyl moieties on the isatin ring, respectively, displayed the highest antiproliferative effects against all four cell lines. These compounds were particularly effective against EBC-1, and HT-29 cells with IC50 values of 3.3-7.1 and 7.3-10.2 μΜ, respectively, while relatively sparing non-cancer cells. The obtained target prediction results suggested that the growth inhibitory activity of the analyzed analogues could be related to tropomyosin receptor kinase C (TrkC) inhibition. The outcomes of molecular docking and MD simulation demonstrated that the most active agents may interact closely with the active site of the suggested target, further confirming target prediction findings. The findings of this study suggest the potential of spiroisatin pyranopyrazole analogues for further exploration as novel targeted anticancer agents.

The macrocyclization of inhibitors has become gradually favored as a new approach for drug design in the field of anticancer agents, since the recent approvals of lorlatinib, pacritinib, and repotrectinib, and feasibility of macrocyclic modification to improve inhibitor drug-like properties has also been confirmed. Macrocycles are receiving increasing attention due to their enhanced binding affinity, target selectivity, and pharmacokinetic properties through conformational constraints. Therefore, this review summarizes various strategies for improving drug-like properties in macrocyclization and structural optimization, and reveals that macrocyclization is a new favorable strategy for drug design, aiming to provide insights for the drug discovery in different targets.

This study aimed to investigate the molecular alterations in primitive neuroectodermal tumors (PNET) of the female genital tract.

We retrospectively analyzed the clinicopathologic and immunohistochemical features of 8 gynecologic PNET cases (3 cervical, 1 vaginal, and 4 ovarian). Fluorescence in situ hybridization and targeted next-generation sequencing (NGS) were performed to identify molecular alterations in these tumors.

The cohort included 5 FIGO stage I, 1 stage III, and 2 stage IV tumors. Two patients with stage IV disease died at 8 and 12 months. The cervical/vaginal tumors consisted of small round blue cells arranged in sheets, with EWSR1 rearrangements and concurrent diffuse expression of membranous CD99 and nuclear FLI1. The ovarian tumors displayed diverse morphologic features resembling central nervous system (CNS) tumors, including embryonal tumor with multilayered rosettes (case 5), medulloblastoma (case 6), glioblastoma (case 7), and ependymoma (case 8). Three ovarian tumors were associated with teratomas. None of the ovarian tumors exhibited EWSR1 rearrangements or i(12p)/12p overrepresentation. NGS identified an EWSR1::exon11∼FLI1::exon6 fusion in one cervical PNET, with no additional molecular alterations. In contrast, three ovarian tumors lacked common genetic changes seen in CNS tumors but harbored several significant variants, including NTRK2 exon11 c.1019C > T (p.T340 M) (case 6), INPP4B exon23 c.2221G > A (p.V741 M) (case 7), and FANCG exon7 c.882_883insA (p.D295Rfs∗14) with MET 7q31 polysomy (case 8).

Our findings confirm that cervical/vaginal and ovarian PNET represent two distinct tumor types. Ovarian PNET have different pathogenetic pathways from their CNS and testicular counterparts most likely.

Gliomas are the most common primary brain tumors characterized by high aggressive potential, poor therapeutic response, and significantly reduced overall patient survival. Despite significant progress in the diagnosis and therapy of cancer, gliomas remain a clinical challenge due to the high molecular and cellular heterogeneity, which provides for multiple mechanisms of chemoresistance and adaptive plasticity. A better understanding of cellular regulatory mechanisms of intracellular signal transduction enables the development of targeted drug therapies and clinical application. The increasing evidence confirms the role of sialoglycans in the processing of cell membrane receptors via altered dimerization, activation, and autophosphorylation, which results in changes in cellular signaling and promotes cancer progression. Hence, the modified sialylation patterns, as a hallmark of cancer, have been described as modulators of chemotherapy effectiveness and drug resistance. The receptor tyrosine kinases (RTKs)-mediated signaling in glial tumors control cell growth, survival, migration, and angiogenesis. Here, we focus on the engagement of the sialome machinery in RTKs processing in gliomas and its importance as a suitable therapeutic target. The analysis of the sialylation pattern and its impact on the activity of growth factor receptors provides valuable insights into our understanding of the molecular and cellular complexity of glial tumors. This highlights the novel treatment approaches that could improve prognosis and patients' overall survival.

Protein kinases are key regulators of cellular processes and critical therapeutic targets in diseases like cancer, making them a focal point for drug discovery efforts. In this context, we developed KinasePred, a robust computational workflow that combines machine learning and explainable artificial intelligence to predict the kinase activity of small molecules while providing detailed insights into the structural features driving ligand-target interactions. Our kinase-family predictive tool demonstrated significant performance, validated through virtual screening, where it successfully identified six kinase inhibitors. Target-focused operational models were subsequently developed to refine target-specific predictions, enabling the identification of molecular determinants of kinase selectivity. This integrated framework not only accelerates the screening and identification of kinase-targeting compounds but also supports broader applications in target identification, polypharmacology studies, and off-target effect analysis, providing a versatile tool for streamlining the drug discovery process.